The present invention relates to prophylactic and therapeutic agents for protozoal disease which comprise plant components having antiprotozoal activity in combination with ionophore antibiotics.
As diseases caused by protozoan parasites, there have been known various kinds of diseases such as avian coccidiosis, coccidiosis in poultry (for example, turkeys and quails), coccidiosis in swine, cattle, sheep and so on, avian leucocytozoon disease, toxoplasmosis, malaria, piroplasmosis, trypanosomiasis and leishmaniasis. As preventive therapeutic agents for such protozoal diseases, there have previously been used sulfa drugs, antithiamine drugs, quinoline derivatives, pyridinol derivatives, nucleic acid derivatives, quinazoline derivatives, guanidine derivatives, folate antagonists, ureal drugs, ionophore antibiotics and the like.
However, as observed in the prevention and treatment of avian coccidiosis, it has recently been revealed that protozoa in the field come to exhibit resistance against these antiprotozoal drugs [MacDougald et al., Avian Diseases 30, 690-694 (1986); Ikeda et al., Collected Summaries of Lectures at 103rd Meeting of Japanese Veterinary Society VI-1, 150 (1987)]. Further, some antiprotozoal drugs have a tendency to remain highly in the bodies of animals to which the drugs have been administered [Drugs for Animals: Remaining of Feed Additives in Animal and Marine Products and Analytical Methods of the Same, Research Institute for Animal Science Biochemistry and Toxicology (1985)]. This fact has been grasped as an important problem on the live-stock industry.
On the other hand, it has recently been revealed that condensed tannins widely contained in higher plants and resin glycosides contained in the plants of the convolvulus family show biological activity to protozoa (Japanese Patent Unexamined Publication Nos. 63-196514/1988 and 63-196523/1988). In addition, plants such as Polgala tenuifolia, Bupleurinum falcatum, Fagara ailanthoides, Uncaria kawakamii, Lycoris radiate and Anemarrhena asphodeloides, and their components have been used for the treatment of diseases such as malaria and amebic dysentery from old times [Kariyone and Kimura, Modern Japanese and Chinese Medicated Botany, published on Sep. 10, 1959]. There have also been handed down Verbena officinalis, Carpesium abratanoides, Artemisia annua and Dichloa febrifuga as antimalarial drugs [Chen Zai Ren, Iconographical Chinese Medicinal Dictionary&lt;Chinese Pharmaceutical Dictionary&gt;, published by Kodansha on May 10, 1982]. However, there is a disadvantage for the application of these plants and their components to livestock animals, when it is considered that these are required to be used in substantial amounts on prescriptions and take a lot of labor for decoction and the like.
Avian coccidiosis, one of protozoal disease, is a disease whose symptom appears by that protozoan parasites of the genus Eimeria, such as mature oocysts of Eimeria tenella, Eimeria necatrix, Eimeria acervulina, Eimeria maxima, Eimeria brunetti and Eimeria mivati, are orally ingested in chickens, parasitized on digestive tracts and propagated. The chickens attacked with the disease excrete diarrheal feces, mucous feces, viscous bloody feces or blood, and lose their vitality and appetite, which cause poor growth, decreased body weight, reduced feed efficiency, reduced resistance against diseases and reduced egg-laying performance during egg-laying periods, and ultimately sometimes cause death. For this reason, this disease has been inflicting an enormous economic damage on the poultry raising industry.
Avian leucocytozoon disease is a disease whose symptom appears due to protozoa Leucocytozoon caulleryi. The chickens attacked with this disease show significant bleeding, hemolysis, harm of hemocytes and the like in their bodies, and therefore exhibit symptoms such as anemia and green feces, which lead to a decrease in body weight, poor growth and a reduction in egg laying, and further cause death. Thus, the damage suffered from this disease is serious.
As to coocidiosis in cattle, conditions suitable for infection are easily produced due to recent new raising methods of beef cattle. Raising cattle exhibit diarrhea, anemia, prostration and a poor appetite, which lead to poor growth.
As exemplified above, diseases caused by protozoa, particularly sporozoa, cause great damage to the live-stock industry such as the cattle raising industry and the poultry raising industry including the chicken raising industry.
There is the disadvantage that sulfa drugs, quinoline derivatives, pyridinol derivatives, nucleic acid derivatives, quinazoline derivatives, diphenylurea derivatives, guanidine derivatives, dinitroimide derivatives, thiamine derivatives, folate antagonists, ionophore antibiotics and the like which have previously been used for the prophylaxis and treatment of such protozoal disease are expensive. In addition, these drugs are facing the serious problem that their original effect is difficult to be expected, because protozoa in the field reduced in sensitivity to the drugs are increasing.
On the other hand, as new ideas, attempts have recently been made to combine ionophore antibiotics particularly selected from the commercially available antiprotozoal drugs with other different kinds of antiprotozoal drugs, or other antibiotics such as mucilin, anthracycline and frenolicin. However, these themselves are strong bioactive substances, so that there is the fear of bioactive expression newly induced by combined administration and unfavorable to animals to which the combined drugs is administered, or of an increase in toxicity. It is therefore necessary to prove that there is not any such fear on practical use. Accordingly, these attempts have difficulty in their application.